Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

Dasheng Lu; Yameng Liu; Yuhong Luo; Jie Zhao; Chao Feng; Liming Xue; Jiale Xu; Qiong Wang; Tingting Yan; Ping Xiao; Kristopher W Krausz; Frank J Gonzalez; Cen Xie

doi:10.1016/j.bbalip.2021.159089

Intestinal farnesoid X receptor signaling controls hepatic fatty acid oxidation

Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb;1867(2):159089. doi: 10.1016/j.bbalip.2021.159089. Epub 2021 Nov 29.

Authors

Dasheng Lu¹, Yameng Liu², Yuhong Luo³, Jie Zhao³, Chao Feng⁴, Liming Xue⁴, Jiale Xu⁴, Qiong Wang³, Tingting Yan³, Ping Xiao⁴, Kristopher W Krausz³, Frank J Gonzalez⁵, Cen Xie⁶

Affiliations

¹ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America; Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
³ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.
⁴ Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China.
⁵ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America. Electronic address: gonzalef@mail.nih.gov.
⁶ Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China. Electronic address: xiecen@simm.ac.cn.

Abstract

In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid β-oxidation (FAO). To explore the different roles of hepatic and intestinal FXR in liver FAO, FAO-associated metabolites, including acylcarnitines and fatty acids, and FXR target gene mRNAs were profiled using an integrated metabolomic and transcriptomic analysis in control (Fxr^fl/fl), liver-specific Fxr-null (Fxr^ΔHep) and intestine-specific Fxr-null (Fxr^ΔIE) mice, treated either with the FXR agonist obeticholic acid (OCA) or vehicle (VEH). Activation of FXR by OCA treatment significantly increased fatty acyl-CoA hydrolysis (Acot1) and decreased FAO-associated mRNAs in Fxr^fl/fl mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr^ΔHep mice responded to OCA treatment in a manner similar to Fxr^fl/fl mice while Fxr^ΔIE mice responded differently, thus illustrating that intestinal FXR plays a critical role in the regulation of hepatic FAO. A significant negative-correlation between intestinal FXR-FGF15 and hepatic CREB-PGC1A pathways was observed after both VEH and OCA treatment, suggesting that OCA-induced activation of the intestinal FXR-FGF15 axis downregulates hepatic PGC1α signaling via inactivation of hepatic CREB, thus repressing FAO. This mechanism was confirmed in experiments based on human recombinant FGF19 treatment and intestinal Fgf15-null mice. This study revealed an important role for the intestinal FXR-FGF15 pathway in hepatic FAO repression.

Keywords: Acylcarnitines; FGF15/19; FXR; Fatty acid oxidation; Metabolomics; PGC1α; Transcriptomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts*

Substances

Bile Acids and Salts

Grants and funding

Z01 BC005562/ImNIH/Intramural NIH HHS/United States